JPH08143449A - Sustained-release local anesthesia injection - Google Patents

Abstract

(57) [Summary] [Purpose] To provide an injection for local anesthesia capable of maintaining a nerve block for a long period of time by sustained-release of a local anesthetic and maintaining a desired therapeutic effect. [Structure] A sustained-release injection for local anesthesia, which comprises a biodegradable carrier containing a local anesthetic such as lidocaine hydrochloride.

Description

Detailed Description of the Invention

[0001]

BACKGROUND OF THE INVENTION 1. Field of the Invention The present invention relates to a sustained-release local anesthetic injection, and more particularly to a sustained-release local anesthetic injection characterized by containing a local anesthetic in a biodegradable carrier. Regarding agents.

[0002]

2. Description of the Related Art In recent years, in the field of pain clinic, so-called nerve block therapy has been performed in which a local anesthetic is locally administered to block nerve transmission. This nerve block therapy has a wide range of applications and is widely used, for example, for controlling cancer pain in patients with end-stage cancer or as an effective therapeutic method for treatment of delayed hypersensitivity such as pollinosis.

In the nerve block therapy currently performed, it is general to administer a local anesthetic by injection as an ordinary injection solution in the vicinity of nerve fibers and ganglia. However, the target site of administration is narrow and the dose is limited, and the drug concentration at the effective site is rapidly decreased due to leakage of the drug solution from the administration site to the surrounding tissues. There is a problem that does not last. as a result,
In order to achieve a certain therapeutic effect, frequent administration of several times to several tens of times may be necessary, which imposes a heavy burden on the patient to be treated. In addition, the procedure is relatively difficult to perform and requires training. In addition, increasing the concentration of local anesthetic to increase the effect may destroy not only nerve fibers but also surrounding tissues. It is not always a convenient treatment for doctors.

[0004]

Means for Solving the Problems As a result of intensive studies to solve the above problems in nerve block therapy, the present inventors have found that collagen, polylactic acid, etc., which are known as biodegradable substances, are used as carriers. An injection obtained by dissolving or dispersing a local anesthetic in this is found to stay at the administration site and release the local anesthetic over a long period of time,
It was confirmed that administration of such sustained-release local anesthesia injection in the vicinity of nerve fibers or ganglia blocks nerve transmission for a long period of time, and as a result, it is possible to maintain the therapeutic effect for a long time with a single administration, The present invention has been completed.

That is, the present invention provides a sustained-release injection for local anesthesia, which is characterized by containing a local anesthetic in a biodegradable carrier. In addition, as a specific embodiment thereof, the following sustained-release injection for local anesthesia is provided. (1) The above-mentioned injection in which the local anesthetic is any one of cocaine, ethyl aminobenzoate, procaine, tetracaine, oxybuprocaine, dibucaine, lidocaine, mepivacaine, oxesazein or an acid addition salt thereof; (2) Local anesthesia The above-mentioned injection in which the drug is lidocaine or its hydrochloride; (3) The carrier is collagen, gelatin, fibrinogen,
The above injection, which is one kind or a mixture of two or more kinds selected from fibrin, polylactic acid, polyglycolic acid and polylactic acid / polyglycolic acid copolymer. Further, the formulation of the present invention also provides the following formulation as an embodiment in view of its use. (4) Injection for sustained release local anesthesia characterized by being used for nerve block; (5) Above injection characterized by being used for stellate ganglion block; (6) Use for epidural block The above injection, characterized by:

[0006] The sustained-release injection for local anesthesia of the present invention is characterized by its sustained effect of nerve block.
Especially, it is expected to be an extremely useful drug in the field of pain clinic.

As the biodegradable carrier in the sustained-release local anesthetic preparation of the present invention, it is known that it is gradually decomposed and metabolized in vivo, has low toxicity, and can be administered in vivo. Molecular compounds are used. Examples of the polymer compound include natural polymers such as collagen, gelatin, albumin, fibrinogen, and fibrin; synthetic polymers such as polylactic acid, polyglycolic acid, and polylactic acid / polyglycolic acid copolymers. Examples include species or a mixture of two or more species.

Of the above-mentioned natural polymers, collagen is a main protein of connective tissue of animals, and is a substance that has little antigenicity and is already widely used for surgical sutures, etc. To enhance collagen, atelocollagen whose enzyme property is further reduced by enzymatic treatment of collagen may be used. Among the above synthetic polymers, polylactic acid / polyglycolic acid copolymer is also a surgical suture "Dexo.
It is used as a material for "n" and its safety has been fully confirmed.

As local anesthetics, naturally occurring coca alkaloids such as cocaine hydrochloride; ethyl aminobenzoate, procaine, tetracaine, oxybuprocaine,
Dibucaine, lidocaine, mepivacaine, bupivacaine, synthetic local anesthetics such as oxesazein, or acid addition salts thereof can be used, among which lidocaine, mepivacaine, bupivacaine, tetracaine or acid addition salts thereof are preferable, and particularly lidocaine or this Hydrochloride is preferable in terms of stability and safety of the obtained injection.

The sustained-release local anesthetic injection of the present invention can be produced by the following methods depending on the kind of the polymer compound used as the carrier. (1) When using a natural polymer When using the above-mentioned natural polymer compound as a biodegradable carrier, first, a local anesthetic (preferably an acid addition salt) is dissolved in an aqueous solution containing the polymer compound, or Suspend uniformly.

In this case, the concentration of the natural polymer compound in the whole preparation is not particularly limited as long as it is within the range of the viscosity which can easily pass through the injection needle upon administration by injection, and the kind of the carrier and the intended sustained duration. Although it can be appropriately changed depending on the sex, it can be generally about 0.1 to 10% by weight, preferably about 0.3 to 7% by weight, and about 0.5 to 5%.
It is particularly preferred that the amount is by weight.

The concentration of the local anesthetic with respect to the whole preparation can be appropriately changed depending on the type and applied disease.
Generally, it can be about 0.1 to 30% by weight, preferably about 0.2 to 20% by weight, particularly preferably about 0.5 to 10% by weight in consideration of safety.

In addition to the above components, the injection of the present invention includes pharmacologically acceptable thickeners such as carboxymethyl cellulose, sodium carboxymethyl cellulose, hyaluronic acid, polyoxyethylene fatty acid ester, polysorbate 80, polyethylene glycol and the like. Stabilizers, antiseptics, bactericides, solubilizers, pH regulators, isotonic agents, etc.
Additives for controlling the decomposition rate of the carrier used can be added as necessary.

The resulting solution or suspension is then filtered and sterilized (eg 0.4
Attach it to a vial etc. by sterilizing it with a 5 μm filter (2 pieces). At this time, if it is directly enclosed in a disposable syringe, it can be conveniently used as a nerve block kit.

(2) When a synthetic polymer is used When the above-mentioned synthetic polymer compound is used as a biodegradable carrier, the polymer compound and a local anesthetic are first dissolved in an appropriate organic solvent such as methylene chloride. Dissolve.
The resulting solution is added to purified water and emulsified by vigorous stirring while distilling off the organic solvent. At this time, the above-mentioned various additives can be added if necessary. The obtained emulsion is freeze-dried and aseptically processed to give a powder formulation. Alternatively, as another method, the synthetic polymer compound and the local anesthetic are heated and melted, and then rapidly cooled with stirring to obtain a molten mixture. The obtained melted mixture is pulverized, the above-mentioned various additives are added if necessary, and aseptic treatment is added to obtain a powder formulation.

In this case, the concentration of the carrier in the whole powder preparation can be appropriately changed depending on the kind of the carrier and the intended durability, but it can generally be about 10-98% by weight, and about 40-. 95% by weight is preferred,
Particularly preferred is about 60-95% by weight. Also,
The concentration of the local anesthetic with respect to the entire powder preparation can be appropriately changed depending on the type and applied disease, but it can generally be about 2 to 90% by weight, preferably about 5 to 60% by weight, Particularly preferred is about 5-40% by weight.

Examples of the aseptic treatment include the γ-ray sterilization method generally used in the pharmaceutical technology.

As described above, when a synthetic polymer is used as a carrier, it can be obtained as a powder formulation, and if it is enclosed in a vial or the like, distilled water for injection is added at the time of use to obtain an aqueous suspension. Injection administration can be performed. The amount of distilled water for injection to be added may be such that the viscosity of the obtained aqueous suspension is within a range that allows injection and administration, and can be appropriately changed depending on the application site and the like, but generally, the powder to be suspended. The amount can be selected from the same amount to about 80 times the weight of the formulation.

The sustained-release injection for local anesthesia of the present invention produced by the above method can be used in the same manner as injecting and administering a local anesthetic in conventional nerve block therapy. The dose is also not particularly limited, but since the local anesthetic has a very long-lasting effect, a relatively small amount, for example, about 1 to 10
ml is capable of continuous targeted nerve block.

The injection of the present invention has a wide range of application. For example, by using it for stellate ganglion block, various diseases can be treated with a single treatment; vascular headache, muscle contraction headache, peripheral facial nerve palsy, cranial nerve. Paralysis, herpes zoster, blood circulation disorder of the upper extremities, periarthritis of the shoulder, bronchial asthma, angina, myocardial infarction, cold, motion sickness, Meniere's disease, stomatitis, irritable bowel syndrome, nervous pollakiuria, cedar and other pollinosis, etc. Suppress pain and symptoms themselves for a long time. Further, by using it in the epidural block, it is possible to strongly suppress the pain such as cancer pain, stone pain, pressure ulcer, postoperative pain, low back pain, burn and the like by a single treatment and to maintain its effect. Furthermore, by using it for the lumbar sympathetic nerve block, it is possible to improve the pain in leg ulcer, rheumatoid arthritis, and knee osteoarthritis with a single treatment.

The sustained effect of the local anesthetic in the injectable composition of the present invention varies depending on the type of polymer used as a carrier in the preparation and the concentration of the local anesthetic. Also, about 10 to 10 when the local anesthetic is locally administered as it is in an aqueous solution or other solution state.
It blocks nerve transmission for a long time of 0 times or more.

[Safety] Among the components used in the sustained-release injection for local anesthesia of the present invention, the carrier itself is an in-vivo component, and its clinical safety has been confirmed.
Further, all of the above-mentioned drugs as local anesthetics are themselves clinically used as injections for local administration, and the use of these drugs in the injection of the present invention has already been confirmed to be safe. It does not exceed the range.

[0023]

EXAMPLES The present invention will be described in more detail below with reference to formulation examples and test examples. Formulation Example 1 To an aqueous solution containing 1.8 g of atelocollagen, 0.6 g of lidocaine hydrochloride and 0.9 g of sodium chloride are added and dissolved. The pH of the resulting solution was adjusted to 7.0 with an aqueous sodium hydroxide solution, and purified water was added to make the total weight of the preparation 100 g.
Was adjusted to obtain the sustained-release local anesthetic injection 1 of the present invention.

Formulation Example 2 According to the method of Formulation Example 1 above, the following Table 1:

[0025]

[Table 1]

Injectable solution 2 with a lidocaine hydrochloride concentration of 2.1% and injectable solution 3 with a concentration of 5% according to the present invention having the formulations shown in Table 1 were obtained.
Further, a sustained-release injection containing no lidocaine hydrochloride was obtained as a control preparation used in the test described below.

Formulation Example 3 According to the method of Formulation Example 1 above, Table 2 below:

[0028]

[Table 2]

Formulations 4 to 6 of the present invention having the formulations shown below were obtained.

Test Example [Method] A male Japanese white rabbit is anesthetized with sodium pentobarbital, the lower part of the Achilles tendon is cut, and its end is connected to an FD pickup. The upper part of the sciatic nerve is exposed and an electrical stimulus is applied to it to measure the tension of the Achilles tendon. Injection 1 obtained in Preparation Example 1 above as a test preparation
Is injected in the vicinity of the unexposed part of the sciatic nerve (between the exposed part and the Achilles tendon) in the same manner as a normal nerve block. As controls, the 0.5% lidocaine hydrochloride aqueous solution and the control preparation obtained in the above Preparation Example 2 were used.

[Result] The tension of the Achilles tendon is 0.5%.
It disappeared for about 30 minutes in the lidocaine hydrochloride aqueous solution, whereas it disappeared for about 13 hours in the preparation 1 of the present invention (containing 0.5% lidocaine hydrochloride). The control formulation containing no lidocaine showed no loss of tension. From the above results, it was confirmed that the nerve block effect of the injection 1 of the present invention lasted about 26 times as long as that of the 0.5% lidocaine hydrochloride aqueous solution. The time required for the tension to disappear increased in proportion to the concentration of lidocaine hydrochloride in the preparation.

─────────────────────────────────────────────────── ─── Continuation of the front page (51) Int.Cl. ⁶ Identification code Office reference number FI Technical indication location A61K 31/445 31/46 AAQ 31/47 47/34 BC 47/42 BC

Claims (4)

[Claims] 1. A sustained-release injection for local anesthesia, which comprises a local anesthetic in a biodegradable carrier. 2. The local anesthetic is any one of cocaine, ethyl aminobenzoate, procaine, tetracaine, oxybuprocaine, dibucaine, lidocaine, mepivacaine, oxesazein or acid addition salts thereof.
The sustained-release injection for local anesthesia described. 3. The sustained-release local anesthetic injection according to claim 1, wherein the local anesthetic is lidocaine or its hydrochloride. 4. The carrier is selected from collagen, gelatin, fibrinogen, fibrin, polylactic acid, polyglycolic acid, and polylactic acid / polyglycolic acid copolymer.
The sustained-release local anesthesia injection according to claim 1, which is one kind or a mixture of two or more kinds.